Macrocytic anemia laboratory findings
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- Measurement of homocysteine and methylmalonic acid can help confirm and differentiate from folate deficiency.
- Both homocysteine and methylmalonic acid are elevated in vitamin B12 deficiency while only homocysteine is elevated in folate deficiency.
- If pernicious anemia is based on low serum level, anti-intrinsic factor antibodies are confirmatory but only present in 50%.
- Anti-parietal cell Abs are more sensitive (90%) but less specific.
Dietary vitamin B12 is bound to factors that are cleaved off by acid leaving vitamin B12 free to bind to R factors secreted by the saliva and gastric juice. Vitamin B12 bound to salivary R factor is not absorbed, but instead requires the alkaline pancreatic secretions and proteases in the duodenum to be freed from R factor. Free vitamin B12 can then bind to intrinsic factor where it is transported to the ileum where a specific receptor then takes up the complex. Therefore, normal vitamin B12 absorption and action are dependent of 5 things:
- Dietary intake (meat and milk)
- Acid in the stomach
- Pancreatic secretions
- Secretion of IF by Gastric parietal cells
- An ileum that can absorb the IF-B12 complex
The Schilling test is designed to test the different components of this system.
- First, 1mg IM B12 is given to saturate transcobalamin.
- Radiolabeled B12 is then given orally.
- If it can be absorbed, then >9% will be excreted in the urine in 24 hours and the rest is eliminated in the feces undetected.
- Renal insufficiency causes a falsely low level.
- It may be spuriously normal in patients without gastrectomy.
- Acid is required to free dietary B12 from binding factors.
- Radiolabeled vitamin B12 is not bound to these factors. Therefore, persons with impaired acid and pepsin production can absorb too little dietary B12, but will absorb free vitamin B12 normally.
Part II of the Schilling test is administering radiolabeled vitamin B12 with IF to see if the problem corrects. This should differentiate pernicious anemia from those with intestinal malabsorption. Vitamin B12 deficiency affects the intestinal mucosal cells and causes malabsorption. Therefore, Part II should only be done 4 weeks after replacement, giving the mucosa time to regenerate in pernicious anemia.
- If Part II is abnormal, Part III is basically a repeat of Part I after a course of antibiotics/vermicides.
- If this is abnormal, an malabsorptive cause is implicated.
The Schilling test was performed in the past to determine the nature of the vitamin B12 deficiency, but due to the lack of available radioactive B12, it is now largely a historical artifact. [[Vitamin B12|Vitamin BTemplate:Ssub]] is a necessary prosthetic group to the enzyme methylmalonyl-coenzyme A mutase. B12 deficiency leads to dysfunction of this enzyme and a buildup of its substrate, methylmalonic acid, the elevated level of which can be detected in the urine and blood. Since the level of methylmalonic acid is not elevated in folic acid deficiency, this test provides a one tool in differentiating the two. However, since the test for elevated methylmalonic acid is not specific enough, the gold standard for the diagnosis of B12 deficiency is a low blood level of B12. Unlike the Shilling test, which often included B12 with intrinsic factor, a low level of blood B12 gives no indication as to the etiology of the low B12, which may result from a number of mechanisms.
MCV is often >110. Hematocrit can often be as low as 15. Elevated LDH and bilirubin are seen since dyserythopoesis leads to destruction of >90% of RBC precursors. Hypersegmentation of PMNs is quite sensitive (>5% with 5 or more lobes or >1% with 6 lobes). Reticulocyte, WBC and platelets are low to normal. In one series of patients with B12 deficiency, 64% had a MCV greater than 100, and only 29% had anemia. In general the blood film can point towards vitamin deficiency:
- Decreased red blood cell (RBC) count and hemoglobin levels
- Increased mean corpuscular volume (MCV >95 fl often >110) and mean corpuscular hemoglobin (MCH)
- The reticulocyte count is normal.
- The platelet count may be reduced.
- Neutrophil granulocytes may show multisegmented nuclei ("senile neutrophil"). This is thought to be due to decreased production and a compensatory prolonged lifespan for circulating neutrophils.
- Anisocytosis (increased variation in RBC size) and poikilocytosis (abnormally shaped RBCs).
- Macrocytes (larger than normal RBCs) are present.
- Ovalocytes (oval shaped RBCs) are present.
- Bone marrow (not normally checked in a patient suspected of megaloblastic anemia) shows megaloblastic hyperplasia.
- Howell-Jolly bodies (chromosomal remnant) also present.
Blood chemistries will also show:
- Increased homocysteine and methylmalonic acid in B12 deficiency
- Increased homocysteine in folate defiency
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